Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Journal of Neuroinflammation

Allison R. Najafi¹  Vivek Swarup¹  Ayer Darling Jue¹  Kim N. Green¹  Sung Jin Kim¹  Lindsay A. Hohsfield¹  Edna E. Hingco¹  Neelakshi Soni¹  Mathew A. Inlay²  Yasamine Ghorbanian² 

[1] Department of Neurobiology and Behavior, University of California, 3208 Biological Sciences III, 92697-4545, Irvine, CA, USA;Sue and Bill Gross Stem Cell Research Center, University of California, 92697, Irvine, CA, USA;Department of Molecular Biology and Biochemistry, University of California, 92697, Irvine, CA, USA;

关键词: Microglia;    Monocytes;    CSF1R inhibition;    Irradiation;    Bone marrow transplant;    Brain;   

DOI  :  10.1186/s12974-020-01931-0

来源: Springer

【 摘 要 】

BackgroundMicroglia, the primary resident myeloid cells of the brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in the CNS is of therapeutic interest.MethodsUsing whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e., monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS.ResultsHere, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1 and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain region-dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripherally derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits.ConclusionsThese findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

【 授权许可】

CC BY